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Review
The value of procalcitonin measurement in localized skin and skin structure infection, diabetic foot infections, septic arthritis and osteomyelitis Expert Rev. Mol. Diagn. 14(1), 47–54 (2014)
Kordo Saeed*1, Nusreen Ahmad2 and Matthew Dryden1 1 Microbiology Department, Hampshire Hospitals NHS Foundation Trust, Royal Hampshire County Hospital, Winchester, UK 2 Public Health England and Southampton University, Hospitals NHS Foundation Trust, Southampton, UK *Author for correspondence: [email protected]
Serum procalcitonin (PCT) is an established diagnostic marker for severe or systemic bacterial infections such as pneumonia, sepsis and septic shock. Data regarding the role of PCT in localized infections without systemic inflammatory response syndrome are scarce. The aim of this review is to assess the value of PCT measurements in localized infections such as skin and skin structure infections, diabetic foot infections, septic arthritis (SA) and osteomyelitis. It appears that serum PCT is unlikely to change the clinical practice in skin and skin structure infection. However, serum PCT could have a role in diagnosis and monitoring of diabetic foot infections in hospitalized settings. There are conflicting reports regarding the ability of serum PCT to distinguish SA from non-SA; synovial PCT may be more appropriate in these settings, including in implant-related infections. Better designed studies are needed to evaluate the usefulness of PCT with or without other biomarkers in localized infections. KEYWORDS: arthritis • diabetic foot infections • localised infections • procalcitonin • septic
Procalcitonin (PCT) is a peptide hormone released by non-neuroendocrine parenchymal cells throughout the body, with serum levels typically 0.2 ng/ml) than in participants with non-infected (0.07 ng/ml) ulcers and controls (0.04 ng/ml). The other main finding of this prospective study was that combining measurements of CRP and PCT increased the accuracy of predicting DFI. ROC analysis for combination of elevated CRP and PCT (0.947 ± 0.029) was significantly greater than that of CRP or PCT alone (p < 0.05) [24]. This finding might help clinicians in everyday practice, contributing to earlier diagnosis and possibly reducing exposure to unnecessary antibiotics. Two more studies also found elevated serum PCT levels in DFI [25,26]. However, this was not the main objective in these studies. Altay et al. [25] looked at the alteration of inflammatory markers including serum PCT, IL-6 and IL-8 levels after treatment in 40 superficial or deep DFI cases, based on the American Diabetes Association definitions 1999 [27]. There was no control group; patients who were receiving efficacious antibiotics beforehand, having a concurrent systemic or local infection, undergoing immunosuppressive therapy, having systemic inflammatory diseases or any organ malignancies were excluded. PCT measurements were made by using Enzyme Linked Fluorescent Assay with the Vidas Brahms PCT (bioMe´rieux, Marcy-l’Etoile, France) kit. The results showed high PCT values for DFI, but without statistical difference in PCT values between superficial infection group and the deep infection group. Interestingly, PCT decreased significantly in the early phase of treatment and healing of DFI. Mutluog˘lu et al. [26] evaluated the use of PCT as an infection marker specifically in the diagnosis of diabetic foot OM in hospitalized patients and compared it with other more commonly used markers, including ESR, WBC and CRP. This study included 24 diabetic persons with infected foot ulcers. Infection was diagnosed according to IDSA guidelines [22]. PCT concentration in serum was measured with an ELISA device (Swallow, SD6015S12M, CIOM Medical Co. Ltd., China) using Human Procalcitonin ELISA kit (Ray Bio, RayBiotech, Inc. Norcross, GA, USA). Although it confirmed that DFIs lead to a marked increase in serum PCT levels, the study did not find a significant difference in terms of PCT levels in diabetic patients with or without OM. Similarly, WBC levels did not differ significantly between diabetic patients with and without OM confirming the finding of Ertugrul et al. who found that WBC levels were similar in diabetic patients with and without OM [28]. These studies are relatively small, very heterogeneous, have different designs and used different PCT test kits. Additionally, www.expert-reviews.com
Review
majority only included hospitalized patients, with no supportive microbiological and/or radiological confirmation for diagnosis of DFI, no appropriate control groups. Additionally, some of the studies excluded individuals who had antibiotics within and up to the previous 6 months; in clinical practice, it is uncommon to have an individual antibiotic free for this period of time within the natural history of DFI. Nevertheless, the results are encouraging and it seems that serum PCT could potentially have a role in DFI; however it does not differentiate OM and severe infections from less severe and soft tissue infection only. Septic arthritis & osteomyelitis
Clinical features of septic (pyogenic or bacterial) arthritis can mimic those of non-SA (e.g., degenerative, crystal and other inflammatory arthritis). Likewise, manifestations of aseptic loosening can resemble those of prosthetic joint infection. Consequently, differentiating various forms of arthritis clinically can prove to be a dilemma for attending clinicians. Traditional serum inflammatory markers are of limited use and studies have shown that the cause of arthritis remains unknown in about 16–36% of patients [29]. Arthrocentesis with synovial gram stain and culture remains the gold standard for SA, with various sensitivity and specificity reports and can take a long time to establish a causative organism. Molecular diagnostics are promising and there are many newer technologies that could be used to diagnose SA [30]. Although PCT is becoming a popular infection biomarker, its role in the diagnosis of SA and OM is still debatable. We found a number of studies that looked at the role of PCT in the diagnosis of SA (TABLE 1) [31–40]. These studies are small, have different designs and objectives and in majority, findings are based on a single serum PCT measurement. In general, it appears that the specificity of serum PCT for infection is high at a cut-off value of ‡0.5 ng/ml, with various reported sensitivities. The variation in sensitivities could be related not only to diagnostic and inclusion criteria, but also due to disparity of PCT assay and cut-off values that have been set, for example, Soderquist et al. and Martinot et al. concluded determination of the serum levels of PCT did not allow the differential diagnosis of SA versus non-SA, particularly in localized infections, but these results are limited by semi-quantitative, low sensitive PCT assay with a functional detection limit of 0.3–0.5 ng/ml and a small and heterogeneous patient cohort not excluding those with concomitant infections [31,32]. Similarly, the low sensitivity in the Butbul-Aviel et al. study could be due to the cut-off level used in the study and the use of a semi-quantitative rapid immunoassay (BRAHMS PCT-Q, Hennigsdorf, Germany) which has a low sensitivity with poor discrimination of values around threshold levels [38]. It also appears that there is lack of microbiological confirmation of SA in most of these studies, which may create a degree of bias, that is, underdiagnosis of SA and wrongly include them in non-SA groups. Although these results are promising, there are insufficient data to support the routine use of serum PCT in the differentiation of SA and non-SA. Lowering the serum 49
50 [32]
[33]
[34]
[35]
[36]
Small number of patients despite involving 8 hospitals for a period of 2 years
Only recruited 30 patients in a 5-year study period. Limitations include long specimen storage time and absence of serum assays for comparison with synovial fluid Small number of patients. Patient characteristics not available, not clear if patients had concomitant positive blood cultures or systemic inflammatory response. Cultures were held for only 48 h, some organisms can take longer to grow Patients with antibiotic treatment or surgery within the last 5 days were excluded. The low number of patients included and the high incidence of coinfections in the non-SA group are main limitations of the study Relatively small number of patients Patients with OA and those received antibiotics prior to enrollment were excluded from the study
Median serum PCT were higher in the SA group (0.7 ng/ml [
Review
The value of procalcitonin measurement in localized skin and skin structure infection, diabetic foot infections, septic arthritis and osteomyelitis Expert Rev. Mol. Diagn. 14(1), 47–54 (2014)
Kordo Saeed*1, Nusreen Ahmad2 and Matthew Dryden1 1 Microbiology Department, Hampshire Hospitals NHS Foundation Trust, Royal Hampshire County Hospital, Winchester, UK 2 Public Health England and Southampton University, Hospitals NHS Foundation Trust, Southampton, UK *Author for correspondence: [email protected]
Serum procalcitonin (PCT) is an established diagnostic marker for severe or systemic bacterial infections such as pneumonia, sepsis and septic shock. Data regarding the role of PCT in localized infections without systemic inflammatory response syndrome are scarce. The aim of this review is to assess the value of PCT measurements in localized infections such as skin and skin structure infections, diabetic foot infections, septic arthritis (SA) and osteomyelitis. It appears that serum PCT is unlikely to change the clinical practice in skin and skin structure infection. However, serum PCT could have a role in diagnosis and monitoring of diabetic foot infections in hospitalized settings. There are conflicting reports regarding the ability of serum PCT to distinguish SA from non-SA; synovial PCT may be more appropriate in these settings, including in implant-related infections. Better designed studies are needed to evaluate the usefulness of PCT with or without other biomarkers in localized infections. KEYWORDS: arthritis • diabetic foot infections • localised infections • procalcitonin • septic
Procalcitonin (PCT) is a peptide hormone released by non-neuroendocrine parenchymal cells throughout the body, with serum levels typically 0.2 ng/ml) than in participants with non-infected (0.07 ng/ml) ulcers and controls (0.04 ng/ml). The other main finding of this prospective study was that combining measurements of CRP and PCT increased the accuracy of predicting DFI. ROC analysis for combination of elevated CRP and PCT (0.947 ± 0.029) was significantly greater than that of CRP or PCT alone (p < 0.05) [24]. This finding might help clinicians in everyday practice, contributing to earlier diagnosis and possibly reducing exposure to unnecessary antibiotics. Two more studies also found elevated serum PCT levels in DFI [25,26]. However, this was not the main objective in these studies. Altay et al. [25] looked at the alteration of inflammatory markers including serum PCT, IL-6 and IL-8 levels after treatment in 40 superficial or deep DFI cases, based on the American Diabetes Association definitions 1999 [27]. There was no control group; patients who were receiving efficacious antibiotics beforehand, having a concurrent systemic or local infection, undergoing immunosuppressive therapy, having systemic inflammatory diseases or any organ malignancies were excluded. PCT measurements were made by using Enzyme Linked Fluorescent Assay with the Vidas Brahms PCT (bioMe´rieux, Marcy-l’Etoile, France) kit. The results showed high PCT values for DFI, but without statistical difference in PCT values between superficial infection group and the deep infection group. Interestingly, PCT decreased significantly in the early phase of treatment and healing of DFI. Mutluog˘lu et al. [26] evaluated the use of PCT as an infection marker specifically in the diagnosis of diabetic foot OM in hospitalized patients and compared it with other more commonly used markers, including ESR, WBC and CRP. This study included 24 diabetic persons with infected foot ulcers. Infection was diagnosed according to IDSA guidelines [22]. PCT concentration in serum was measured with an ELISA device (Swallow, SD6015S12M, CIOM Medical Co. Ltd., China) using Human Procalcitonin ELISA kit (Ray Bio, RayBiotech, Inc. Norcross, GA, USA). Although it confirmed that DFIs lead to a marked increase in serum PCT levels, the study did not find a significant difference in terms of PCT levels in diabetic patients with or without OM. Similarly, WBC levels did not differ significantly between diabetic patients with and without OM confirming the finding of Ertugrul et al. who found that WBC levels were similar in diabetic patients with and without OM [28]. These studies are relatively small, very heterogeneous, have different designs and used different PCT test kits. Additionally, www.expert-reviews.com
Review
majority only included hospitalized patients, with no supportive microbiological and/or radiological confirmation for diagnosis of DFI, no appropriate control groups. Additionally, some of the studies excluded individuals who had antibiotics within and up to the previous 6 months; in clinical practice, it is uncommon to have an individual antibiotic free for this period of time within the natural history of DFI. Nevertheless, the results are encouraging and it seems that serum PCT could potentially have a role in DFI; however it does not differentiate OM and severe infections from less severe and soft tissue infection only. Septic arthritis & osteomyelitis
Clinical features of septic (pyogenic or bacterial) arthritis can mimic those of non-SA (e.g., degenerative, crystal and other inflammatory arthritis). Likewise, manifestations of aseptic loosening can resemble those of prosthetic joint infection. Consequently, differentiating various forms of arthritis clinically can prove to be a dilemma for attending clinicians. Traditional serum inflammatory markers are of limited use and studies have shown that the cause of arthritis remains unknown in about 16–36% of patients [29]. Arthrocentesis with synovial gram stain and culture remains the gold standard for SA, with various sensitivity and specificity reports and can take a long time to establish a causative organism. Molecular diagnostics are promising and there are many newer technologies that could be used to diagnose SA [30]. Although PCT is becoming a popular infection biomarker, its role in the diagnosis of SA and OM is still debatable. We found a number of studies that looked at the role of PCT in the diagnosis of SA (TABLE 1) [31–40]. These studies are small, have different designs and objectives and in majority, findings are based on a single serum PCT measurement. In general, it appears that the specificity of serum PCT for infection is high at a cut-off value of ‡0.5 ng/ml, with various reported sensitivities. The variation in sensitivities could be related not only to diagnostic and inclusion criteria, but also due to disparity of PCT assay and cut-off values that have been set, for example, Soderquist et al. and Martinot et al. concluded determination of the serum levels of PCT did not allow the differential diagnosis of SA versus non-SA, particularly in localized infections, but these results are limited by semi-quantitative, low sensitive PCT assay with a functional detection limit of 0.3–0.5 ng/ml and a small and heterogeneous patient cohort not excluding those with concomitant infections [31,32]. Similarly, the low sensitivity in the Butbul-Aviel et al. study could be due to the cut-off level used in the study and the use of a semi-quantitative rapid immunoassay (BRAHMS PCT-Q, Hennigsdorf, Germany) which has a low sensitivity with poor discrimination of values around threshold levels [38]. It also appears that there is lack of microbiological confirmation of SA in most of these studies, which may create a degree of bias, that is, underdiagnosis of SA and wrongly include them in non-SA groups. Although these results are promising, there are insufficient data to support the routine use of serum PCT in the differentiation of SA and non-SA. Lowering the serum 49
50 [32]
[33]
[34]
[35]
[36]
Small number of patients despite involving 8 hospitals for a period of 2 years
Only recruited 30 patients in a 5-year study period. Limitations include long specimen storage time and absence of serum assays for comparison with synovial fluid Small number of patients. Patient characteristics not available, not clear if patients had concomitant positive blood cultures or systemic inflammatory response. Cultures were held for only 48 h, some organisms can take longer to grow Patients with antibiotic treatment or surgery within the last 5 days were excluded. The low number of patients included and the high incidence of coinfections in the non-SA group are main limitations of the study Relatively small number of patients Patients with OA and those received antibiotics prior to enrollment were excluded from the study
Median serum PCT were higher in the SA group (0.7 ng/ml [
